PROJECT SUMMARY Immune signaling plays an important role in initiation of inflammatory responses, resolution of acute tissue damage, and adaptation to chronic stress. Although inflammatory pathways responding to pathogens are well characterized, mechanisms mediating metabolic adaptation to cope with energy demands of various immune functions have just been realized in recent years. Upon activation by inflammatory stimuli, macrophages display a shift in energy utilization in favor of aerobic glycolysis with a diversion of pyruvate toward lactate production and away from further oxidation by mitochondria (known as the Warburg effect). Increased glucose uptake supports the acute energetic needs of activated macrophages. While the adaptation in energy metabolism (in part, regulated by Hif-1?) is essential to mount an effective pro-inflammatory response, this process also rapidly dampens mitochondrial respiration, which may lead to a progressive energy deficit. Consequently, increased macrophage dysfunction and death has been associated with severe sepsis and poor disease outcome in rodent models and humans. Currently, little is known concerning mechanisms that restore mitochondrial metabolic function in inflammatory macrophages and whether this is necessary to limit inflammatory dysfunction. Preliminary results show that in the macrophage pro-inflammatory stimuli, such as acute LPS treatment or Ifn?-primed, chronic LPS challenge (or M1 activation), induce the expression of Bmal1, a master regulator of circadian rhythm. Using myeloid-specific Bmal1 knockout (M-Bmal1KO) mice, our results suggest that this ?resetting? of the molecular clock following inflammatory stimulation facilitates the restoration of mitochondrial oxidative metabolism and cellular function. In addition, Bmal1 physically and functionally interacts with Hif-1?. We will test the hypothesis that crosstalk between Bmal1 and Hif1? serves as a molecular switch that controls energy utilization from glycolytic to oxidative metabolism in inflammatory macrophages. Interestingly, both circadian regulation and Hif-1? accumulation in peripheral tissues are dysregulated in obesity and with age. Therefore, results derived from the research plan may have important implications in obesity- and age-related inflammatory dysfunction.